Donald D. Hensrud

Valvular heart disease associated with fenfluramine phentermine

BACKGROUND Fenfluramine and phentermine have been individually approved as anorectic agents by the Food and Drug Administration (FDA). When used in combination the drugs may be just as effective as either drug alone, with the added advantages of the need for lower doses of each agent and perhaps fewer side effects. Although the combination has not been approved by the FDA, in 1996 the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million. METHODS We identified valvular heart disease in 24 women treated with fenfluramine-phentermine who had no history of cardiac disease. The women presented with cardiovascular symptoms or a heart murmur. As increasing numbers of these patients with similar clinical features were identified, there appeared to be an association between these features and fenfluramine-phentermine therapy. RESULTS Twenty-four women (mean [+/-SD] age, 44+/-8 years) were evaluated 12.3+/-7.1 months after the initiation of fenfluramine-phentermine therapy. Echocardiography demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved. Eight women also had newly documented pulmonary hypertension. To date, cardiac surgical intervention has been required in five patients. The heart valves had a glistening white appearance. Histopathological findings included plaque-like encasement of the leaflets and chordal structures with intact valve architecture. The histopathological features were identical to those seen in carcinoid or ergotamine-induced valve disease. CONCLUSIONS These cases arouse concern that fenfluramine-phentermine therapy may be associated with valvular heart disease. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease.

Splanchnic lipolysis in human obesity.

Elevated FFA concentrations have been shown to reproduce some of the metabolic abnormalities of obesity. It has been hypothesized that visceral adipose tissue lipolysis releases excess FFAs into the portal vein, exposing the liver to higher FFA concentrations. We used isotope dilution/hepatic vein catheterization techniques to examine whether intra-abdominal fat contributes a greater portion of hepatic FFA delivery in visceral obesity. Obese women (n = 24) and men (n = 20) with a range of obesity phenotypes, taken together with healthy, lean women (n = 12) and men (n = 12), were studied. Systemic, splanchnic, and leg FFA kinetics were measured. The results showed that plasma FFA concentrations were approximately 20% greater in obese men and obese women. The contribution of splanchnic lipolysis to hepatic FFA delivery ranged from less than 10% to almost 50% and increased as a function of visceral fat in women (r = 0.49, P = 0.002) and in men (r = 0.52, P = 0.002); the slope of the relationship was greater in women than in men (P < 0.05). Leg and splanchnic tissues contributed a greater portion of systemic FFA release in obese men and women than in lean men and women. We conclude that the contribution of visceral adipose tissue lipolysis to hepatic FFA delivery increases with increasing visceral fat in humans and that this effect is greater in women than in men.

Vitamin D Deficiency : An Important, Common, and Easily Treatable Cardiovascular Risk Factor?

Vitamin D deficiency is a highly prevalent condition, present in approximately 30% to 50% of the general population. A growing body of data suggests that low 25-hydroxyvitamin D levels may adversely affect cardiovascular health. Vitamin D deficiency activates the renin-angiotensin-aldosterone system and can predispose to hypertension and left ventricular hypertrophy. Additionally, vitamin D deficiency causes an increase in parathyroid hormone, which increases insulin resistance and is associated with diabetes, hypertension, inflammation, and increased cardiovascular risk. Epidemiologic studies have associated low 25-hydroxyvitamin D levels with coronary risk factors and adverse cardiovascular outcomes. Vitamin D supplementation is simple, safe, and inexpensive. Large randomized controlled trials are needed to firmly establish the relevance of vitamin D status to cardiovascular health. In the meanwhile, monitoring serum 25-hydroxyvitamin D levels and correction of vitamin D deficiency is indicated for optimization of musculoskeletal and general health.

State-of-the-Art PaperVitamin D Deficiency: An Important, Common, and Easily Treatable Cardiovascular Risk Factor?

Vitamin D deficiency is a highly prevalent condition, present in approximately 30% to 50% of the general population. A growing body of data suggests that low 25-hydroxyvitamin D levels may adversely affect cardiovascular health. Vitamin D deficiency activates the renin-angiotensin-aldosterone system and can predispose to hypertension and left ventricular hypertrophy. Additionally, vitamin D deficiency causes an increase in parathyroid hormone, which increases insulin resistance and is associated with diabetes, hypertension, inflammation, and increased cardiovascular risk. Epidemiologic studies have associated low 25-hydroxyvitamin D levels with coronary risk factors and adverse cardiovascular outcomes. Vitamin D supplementation is simple, safe, and inexpensive. Large randomized controlled trials are needed to firmly establish the relevance of vitamin D status to cardiovascular health. In the meanwhile, monitoring serum 25-hydroxyvitamin D levels and correction of vitamin D deficiency is indicated for optimization of musculoskeletal and general health.

Vitamin D and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

CONTEXT Several studies found association between vitamin D levels and hypertension, coronary artery calcification, and heart disease. OBJECTIVE The aim of this study was to summarize the evidence on the effect of vitamin D on cardiovascular outcomes. DESIGN AND METHODS We searched electronic databases from inception through August 2010 for randomized trials. Reviewers working in duplicate and independently extracted study characteristics, quality, and the outcomes of interest. Random-effects meta-analysis was used to pool the relative risks (RR) and the weighted mean differences across trials. RESULTS We found 51 eligible trials with moderate quality. Vitamin D was associated with nonsignificant effects on the patient-important outcomes of death [RR, 0.96; 95% confidence interval (CI), 0.93, 1.00; P = 0.08], myocardial infarction (RR, 1.02; 95% CI, 0.93, 1.13; P = 0.64), and stroke (RR, 1.05; 95% CI, 0.88, 1.25; P = 0.59). These analyses were associated with minimal heterogeneity. There were no significant changes in the surrogate outcomes of lipid fractions, glucose, or diastolic or systolic blood pressure. The latter analyses were associated with significant heterogeneity, and the pooled estimates were trivial in absolute terms. CONCLUSIONS Trial data available to date are unable to demonstrate a statistically significant reduction in mortality and cardiovascular risk associated with vitamin D. The quality of the available evidence is low to moderate at best.

The Effect of Vitamin D on Falls: A Systematic Review and Meta-Analysis

CONTEXT Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly. OBJECTIVE The aim of this systematic review is to summarize the existing evidence on vitamin D use and the risk of falls. DATA SOURCES We searched electronic databases from inception through August 2010. STUDY SELECTION Eligible studies were randomized controlled trials in which the intervention was vitamin D and the incidence of falls was reported. DATA EXTRACTION Reviewers working in duplicate and independently extracted study characteristics, quality, and outcomes data. DATA SYNTHESIS Odds ratio and associated 95% confidence interval were estimated from each study and pooled using the random effects model. RESULTS We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96). This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D. The quality of evidence was low to moderate because of heterogeneity and publication bias. CONCLUSIONS Vitamin D combined with calcium reduces the risk of falls. The reduction in studies without calcium coadministration did not reach statistical significance. The majority of the evidence is derived from trials enrolling elderly women.

The effect of vitamin D on falls

CONTEXT Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly. OBJECTIVE The aim of this systematic review is to summarize the existing evidence on vitamin D use and the risk of falls. DATA SOURCES We searched electronic databases from inception through August 2010. STUDY SELECTION Eligible studies were randomized controlled trials in which the intervention was vitamin D and the incidence of falls was reported. DATA EXTRACTION Reviewers working in duplicate and independently extracted study characteristics, quality, and outcomes data. DATA SYNTHESIS Odds ratio and associated 95% confidence interval were estimated from each study and pooled using the random effects model. RESULTS We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96). This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D. The quality of evidence was low to moderate because of heterogeneity and publication bias. CONCLUSIONS Vitamin D combined with calcium reduces the risk of falls. The reduction in studies without calcium coadministration did not reach statistical significance. The majority of the evidence is derived from trials enrolling elderly women.

Extreme Obesity: A New Medical Crisis in the United States

The prevalence of obesity has markedly increased in the past few decades, and this disorder is responsible for more health care expenditures than any other medical condition. The greater the body mass index (BMI) (calculated as weight in kilograms divided by the square of height in meters), the greater the risk of comorbidities, including diabetes mellitus, hypertension, obstructive sleep apnea, many cancers, dyslipidemia, cardiovascular disease, and overall mortality. Class III (extreme) obesity, defined as a BMI of 40 kg/m2 or greater, has also increased such that it now affects almost 1 in 20 Americans. The prevalence of extreme obesity is greater among women than among men and greater among blacks than among non-Hispanic whites or Hispanics. The effect of extreme obesity on mortality is greater among young than among older adults, greater among men than among women, and greater among whites than among blacks. The current permissive environment that promotes increased dietary energy intake and decreased energy expenditure through reduced daily physical activity coupled with genetic susceptibility is an important pathogenic factor. The number of bariatric surgical procedures performed annually is relatively small but increasing.

Metabolic predictors of obesity. Contribution of resting energy expenditure, thermic effect of food, and fuel utilization to four-year weight gain of post-obese and never-obese women.

This prospective study was designed to identify abnormalities of energy expenditure and fuel utilization which distinguish post-obese women from never-obese controls. 24 moderately obese, postmenopausal, nondiabetic women with a familial predisposition to obesity underwent assessments of body composition, fasting and postprandial energy expenditure, and fuel utilization in the obese state and after weight loss (mean 12.9 kg) to a post-obese, normal-weight state. The post-obese women were compared with 24 never-obese women of comparable age and body composition. Four years later, without intervention, body weight was reassessed in both groups. Results indicated that all parameters measured in the post-obese women were similar to the never-obese controls: mean resting energy expenditure, thermic effect of food, and fasting and postprandial substrate oxidation and insulin-glucose patterns. Four years later, post-obese women regained a mean of 10.9 kg while control subjects remained lean (mean gain 1.7 kg) (P < 0.001 between groups). Neither energy expenditure nor fuel oxidation correlated with 4-yr weight changes, whereas self-reported physical inactivity was associated with greater weight regain. The data suggest that weight gain in obesity-prone women may be due to maladaptive responses to the environment, such as physical inactivity or excess energy intake, rather than to reduced energy requirements.

Underreporting the Use of Dietary Supplements and Nonprescription Medications Among Patients Undergoing a Periodic Health Examination

OBJECTIVE To compare the use of dietary supplements and nonprescription medications as reported on a written medical questionnaire with use reported during a structured interview. DESIGN We conducted a prospective study of 200 subjects randomly selected among patients undergoing a periodic health examination in two divisions of the Department of Internal Medicine at Mayo Clinic Rochester--100 patients from a national cohort of executives and 100 community patients. MATERIAL AND METHODS Written information on self-reported use of supplements and nonprescription medications was obtained as part of a comprehensive medical questionnaire. Subjects were then interviewed and asked about the use of supplements and nonprescription medications. In addition, the reason for using supplements was elicited and recorded. RESULTS The prevalence of use of dietary supplements was 30.5% by written self-report in comparison with 61.0% reported during the structured interview. The results were consistent between executive and community patients. In response to questions about taking nonprescription medications, 24.5% of patients reported such use on the medical questionnaire in comparison with 42.5% when interviewed. The most common dietary supplements taken were multivitamins (41.5%), followed by vitamin E (24.0%) and vitamin C (23.0%). The most common nonprescription medications taken were aspirin (16.5%) and ibuprofen (13.0%). Most frequently, patients indicated that they were using supplements to promote health. CONCLUSION In this study, half the patients who took dietary supplements and almost half who took nonprescription medications did not report them to their healthcare provider on a written questionnaire, even though this information was requested. Patients should be specifically asked about use of dietary supplements and nonprescription medications, even if written information about such use is provided.